tbuckley/cabot-search huggingface dataset:
Transcriptomic signatures of chronic active antibody-mediated rejection deciphered by RNA sequencing of human kidney allografts
Authors: Yajas Shah, Hua Yang, Franco B. Mueller, Carol Li, Shab E. Gul Rahim, Elly Varma, Thalia Salinas, Darshana M. Dadhania, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar
Journal: Kidney International (2023)

Natural killer (NK) cells mediate spontaneous cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. This dual functionality could enable their participation in chronic active antibody-mediated rejection (CA-ABMR). Earlier microarray profiling studies have not subcategorized antibody-mediated rejection into CA-ABMR and active-ABMR, and the gene expression pattern of CA-ABMR has not been compared with that of T cell-mediated rejection (TCMR). To fill these gaps, we RNA sequenced human kidney allograft biopsies categorized as CA-ABMR, active-ABMR, TCMR, or No Rejection (NR). Among the 15,910 genes identified in the biopsies, 60, 114, and 231 genes were uniquely overexpressed in CA-ABMR, TCMR, and active-ABMR, respectively, compared to NR, 50 genes were shared between CA-ABMR and active-ABMR, and 164 genes between CA-ABMR and TCMR. The overexpressed genes were annotated to NK cells and T cells in CA-ABMR and TCMR, and to neutrophils and monocytes in active-ABMR. The NK cell cytotoxicity and allograft rejection pathways were enriched in CA-ABMR. Genes encoding perforin, granzymes, and death receptor, were overexpressed in CA-ABMR versus ABMR but not compared to TCMR. NK cell cytotoxicity pathway gene set variation analysis score was higher in CA-ABMR compared to active-ABMR but not in TCMR. Principal component analysis of the deconvolved immune cellular transcriptomes separated CA-ABMR and TCMR from active-ABMR and NR. Immunohistochemistry of kidney allograft biopsies validated a higher proportion of CD56+ NK cells in CA-ABMR than in active-ABMR. Thus, CA-ABMR was exemplified by the overexpression of the NK cell cytotoxicity pathway gene set and, surprisingly, molecularly more like TCMR than active-ABMR.
Moderate and vigorous leisure time physical activity in older adults and Alzheimer's disease-related mortality in the USA: a dose–response, population-based study
Authors: Rubén López-Bueno, Lin Yang, Emmanuel Stamatakis, Borja del Pozo Cruz
Journal: The Lancet Healthy Longevity (2023)

BackgroundData for the dose–response associations of moderate physical activity (MPA) and vigorous physical activity (VPA) with Alzheimer's disease-related mortality are scarce. We aimed to examine the prospective associations of such activity with Alzheimer's disease-related mortality.MethodsIn this dose–response, population-based study, we pooled data from 22 consecutive waves of the US National Health Interview Survey (from 1997 to 2018). Participants aged 68 years or older were included in the study if they had full data for physical or muscle-strengthening activity, chronic conditions, functional limitations, marital status, education level, alcohol consumption, smoking status, and BMI, and follow-up time after study entry. Participants were linked to the National Death Index until Dec 31, 2019. We defined Alzheimer's disease-related mortality as a leading cause by using the G-30 code of the International Statistical Classification of Diseases and Related Health Problems tenth revision. Information on MPA and VPA was self-reported, with participants asked to answer four questions on the frequency and duration of both types of physical activity. We calculated hazard ratios (HRs) and used restricted cubic splines models to assess dose–response associations, and we estimated the annual number of Alzheimer's disease-related deaths that could be prevented through physical activity using adjusted population attributable fractions.FindingsAfter excluding 21 377 participants, 91 298 adults were included in the analysis. The weighted mean participant age was 75·8 years (SE 0·0); 55 658 (56·7%) were female and 76 796 (87·6%) were White (weighted percentages). The median follow-up was 6·5 years (IQR 3·6–10·7), corresponding to 703 393 person-years. 2176 (2·4%) participants died due to Alzheimer's disease as the leading cause. For MPA, we did not find a significant dose–response association with Alzheimer's disease-related mortality, whereas for VPA, we observed a significant L-shaped association between 20 weekly min and 190 weekly min. For VPA, we identified a minimal amount (ie, 50% of the optimal amount) at 40 min/week (HR 0·91, 95% CI 0·84–0·95) and an optimal amount (ie, the nadir of the curve) at 140 min/week (0·79, 0·66–0·95) for reducing Alzheimer's disease-related mortality. For the USA, we estimated that 40 weekly min of VPA would prevent 12 238 deaths per year (95% CI 89–23 172) and 140 weekly min of VPA would prevent 37 710 deaths per year (311–63 567), compared with a scenario in which US adults did not do any VPA.InterpretationThese findings might inform future guidelines for preventing Alzheimer's disease-related mortality by emphasising the importance of VPA over MPA and providing specific VPA targets.FundingNone.
Diabetes Risk Factors and Bone Microarchitecture as Assessed by High-Resolution Peripheral Quantitative Computed Tomography in Adults With Long-standing Type 1 Diabetes
Authors: Naina Sinha Gregory, Andrew J. Burghardt, Jye-Yu C. Backlund, Mishaela R. Rubin, Ionut Bebu, Barbara H. Braffett, David J. Kenny, Thomas M. Link, Galateia J. Kazakia, Annette Barnie, John M. Lachin, Rose Gubitosi-Klug, Ian H. de Boer, Ann V. Schwartz
Journal: Diabetes Care (2023)

To determine whether type 1 diabetes and its complications are associated with bone geometry and microarchitecture.
Risk factors and outcomes of melanoma in children and adolescents: A retrospective multicenter study
Authors: Elena B. Hawryluk, Danna Moustafa, Kelly K. Barry, Eman Bahrani, Diana B. Reusch, Meera Brahmbhatt, Lily Chen, Carrie C. Coughlin, Pedram Gerami, Ellen Haddock, Kristen Hook, Stephen R. Humphrey, Pei-Chi Kao, Lacey L. Kruse, Leslie P. Lawley, Danny Mansour, Ashfaq A. Marghoob, Julie Nguyen, Thuy L. Phung, Elena Pope, Tom Raisanen, Sarah Robinson, Tova Rogers, Birgitta Schmidt, Gary Tran, Kate Travis, Zachary Wolner, Wendy B. London, Lawrence F. Eichenfield, Jennifer Huang
Journal: Journal of the American Academy of Dermatology (2023)
The Importance of Randomized, Controlled Trials in the Care of Organ Donors
Authors: Kiran K. Khush
Journal: New England Journal of Medicine (2023)

The persistent scarcity of available donor hearts demands concerted efforts to expand the pool of donors and maximize their use for heart transplantation. Central to this goal is appropriate care for brain-dead donors as performed by organ-procurement organizations (OPOs) and guided by consensus protocols.1,2 Although decades old and incompletely aligned, these protocols generally recommend the use of intravenous thyroid hormone, particularly in donors with left ventricular dysfunction or hemodynamic instability. Accordingly, such use of thyroid hormone supplementation has become commonplace. The rationale for thyroid hormone supplementation stems from the profound physiological changes that occur after brain death. After brain-stem herniation, . . .
A Deficient Diagnosis
Authors: Alison E. Burke, Leslie Chang, Ann Cheung, Emily Ling, Caren G. Solomon, Scott Williams
Journal: New England Journal of Medicine (2023)

This Double Take video from the New England Journal of Medicine presents the case of a toddler with a limp. Based on a Clinical Problem-Solving article published in the Journal, the video explores the differential diagnosis for a child refusing to bear weight on his right leg and follows its evolution as new clinical findings arise from the diagnostic evaluation. For further reading, the following article, referenced in this video, is available at NEJM.org: A Deficient Diagnosis (Hafez et al., in the April 7, 2016, issue).
Oral Contraceptives for Menstrual Migraine with Aura
Authors: Clement D. Lee, Rossella E. Nappi, Carrie Cwiak
Journal: New England Journal of Medicine (2023)

This feature about a woman who has migraines with aura, usually occurring around the time of her menses, offers a case vignette accompanied by two essays, one supporting prescription of oral combined contraceptive pills and the other recommending against it.
Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors
Authors: Rajat Dhar, Gary F. Marklin, W. Dean Klinkenberg, Jinli Wang, Charles W. Goss, Abhijit V. Lele, Clark D. Kensinger, Paul A. Lange, Daniel J. Lebovitz
Journal: New England Journal of Medicine (2023)

Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation. Download a PDF of the Research Summary. In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 μg per hour for a minimum of 12 hours) or saline placebo. The primary outcome was transplantation of the donor heart; graft survival at 30 days after transplantation was a prespecified recipient safety outcome. Secondary outcomes included weaning from vasopressor therapy, donor ejection fraction, and number of organs transplanted per donor. Of the 852 brain-dead donors who underwent randomization, 838 were included in the primary analysis: 419 in the levothyroxine group and 419 in the saline group. Hearts were transplanted from 230 donors (54.9%) in the levothyroxine group and 223 (53.2%) in the saline group (adjusted risk ratio, 1.01; 95% confidence interval [CI], 0.97 to 1.07; P=0.57). Graft survival at 30 days occurred in 224 hearts (97.4%) transplanted from donors assigned to receive levothyroxine and 213 hearts (95.5%) transplanted from donors assigned to receive saline (difference, 1.9 percentage points; 95% CI, −2.3 to 6.0; P<0.001 for noninferiority at a margin of 6 percentage points). There were no substantial between-group differences in weaning from vasopressor therapy, ejection fraction on echocardiography, or organs transplanted per donor, but more cases of severe hypertension and tachycardia occurred in the levothyroxine group than in the saline group. In hemodynamically unstable brain-dead potential heart donors, intravenous levothyroxine infusion did not result in significantly more hearts being transplanted than saline infusion. (Funded by Mid-America Transplant and others; ClinicalTrials.gov number, NCT04415658.) QUICK TAKE VIDEO SUMMARYLevothyroxine and Heart Donation 01:50
Case 37-2023: A 29-Year-Old Man with Sickle Cell Disease and Right Hip Pain
Authors: Sharl S. Azar, F. Joseph Simeone, Jana Jarolimova, E. Zachary Nussbaum
Journal: New England Journal of Medicine (2023)

A 29-year-old man with sickle cell disease, which had been complicated by vaso-occlusive events and osteonecrosis leading to hip arthroplasty, was admitted because of hip pain. A diagnosis was made.
Pre–Covid-19, SARS-CoV-2–Negative Multisystem Inflammatory Syndrome in Children
Authors: Sarah Benezech, Liliane Khoryati, Jade Cognard, Stejara A Netea, Taushif Khan, Marion Moreews, Kahina Saker, Jean-Marie De Guillebon, Samira Khaldi-Plassart, Rémi Pescarmona, Sebastien Viel, Christophe Malcus, Magali Perret, Meriadeg Ar Gouilh, Astrid Vabret, Fabienne Venet, Solenn Remy, Emilie Chopin, Gérard Lina, François Vandenesch, Noëmi Rousseaux, Paul Bastard, Shen-Ying Zhang, Jean-Laurent Casanova, Sophie Trouillet-Assant, Thierry Walzer, Taco W Kuijpers, Etienne Javouhey, Olivier Dauwalder, Nico Marr, Alexandre Belot
Journal: New England Journal of Medicine (2023)
Immunocompetent PDMS‐Free Organ‐on‐Chip Model of Cervical Cancer Integrating Patient‐Specific Cervical Fibroblasts and Neutrophils
Authors: Elena Kromidas, Alicia Geier, Adrian Weghofer, Hui‐Yu Liu, Martin Weiss, Peter Loskill
Journal: Advanced Healthcare Materials (2023)

Despite preventive measures and available treatments, cervical cancer still ranks as the fourth most prevalent cancer among women worldwide and remains the leading cause of cancer death in women in many developing countries. To gain further insights into pathogenesis and to develop novel (immuno)therapies, more sophisticated human models recreating patient heterogeneities and including aspects of the tumor microenvironment are urgently required. A novel polydimethylsiloxane-free microfluidic platform, designed specifically for the generation and ccultivation of cervical cancerous tissue, is introduced. The microscale open-top tissue chambers of the cervical cancer-on-chip (CCoC) enable facile generation and long-term cultivation of SiHa spheroids in co-culture with donor-derived cervical fibroblasts. The resulting 3D tissue emulates physiological architecture and allows dissection of distinct effects of the stromal tissue on cancer viability and growth. Treatment with cisplatin at clinically-relevant routes of administration and dosing highlights the platform's applicability for drug testing. Moreover, the model is amenable for integration and recruitment of donor-derived neutrophils from the microvasculature-like channel into the tissue, all while retaining their ability to produce neutrophil extracellular traps. In the future, the immunocompetent CCoC featuring donor-specific primary cells and tumor spheroids has the potential to contribute to the development of new (immuno)therapeutic options.
Hybrid interpenetrating network of polyester coronary stent with tunable biodegradation and mechanical properties
Authors: Daokun Shi, Yahong Kang, Zailai Jiang, Xin Li, Hongjie Zhang, Qunsong Wang, Jingzhen Guo, Hongyan Jiang, Qiyi Luo, Jiandong Ding
Journal: Biomaterials (2023)
Intraprocedural Doppler and Invasive Hemodynamic Profiling Predict Clinical Outcomes After Mitral TEER
Authors: Syed Zaid, Priscilla Wessly, Taha Hatab, Nadeen Faza, Stephen H. Little, Marvin D. Atkins, Michael J. Reardon, Neal S. Kleiman, William A. Zoghbi, Sachin S. Goel
Journal: JACC. Cardiovascular imaging (2023)
Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Caroline J. Coats, Martin S. Maron, Theodore P. Abraham, Iacopo Olivotto, Matthew M.Y. Lee, Michael Arad, Nuno Cardim, Chang-Sheng Ma, Lubna Choudhury, Hans-Dirk Düngen, Pablo Garcia-Pavia, Albert A. Hagège, Gregory D. Lewis, Michelle Michels, Artur Oreziak, Anjali T. Owens, Jacob Tfelt-Hansen, Josef Veselka, Hugh C. Watkins, Stephen B. Heitner, Daniel L. Jacoby, Stuart Kupfer, Fady I. Malik, Lisa Meng, Amy Wohltman, Ahmad Masri
Journal: JACC Heart Failure (2023)

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).
The effect of a bionic bone ionic environment on osteogenesis, osteoimmunology, and in situ bone tissue engineering
Authors: Yuqing Mu, Zhibin Du, Wendong Gao, Lan Xiao, Ross Crawford, Yin Xiao
Journal: Biomaterials (2023)

Bone, a mineralized tissue, continuously undergoes remodeling, a process that engages the mineralization and demineralization of the bone matrix, orchestrated by the interactions among cells and cell-secreted biomolecules under the bone ionic microenvironment. The osteoinductive properties of the demineralized organic bone matrix and many biological factors have been well-investigated. However, the impact of the bone ionic environment (BIE) on cell differentiation and osteogenesis remains largely unknown. In this study, we extracted and isolated inorganic bone components (bone-derived monetite, BM) using a low-temperature method and, for the first time, investigated whether the BIE could actively affect cell differentiation and regulate osteoimmune reactions. It was evidenced that the BIE could foster the osteogenesis of human bone marrow stromal cells (hBMSCs) and promote hBMSCs mineralization without using osteogenic inductive agents. Interestingly, it was noted that BIE resulted in intracellular mineralization, evidenced by intracellular accumulation of carbonate hydroxyapatite similar to osteoblasts cultured in the osteoinductive media. Additionally, BIE was found to enhance osteogenesis by generating a favorable osteoimmune environment. In a rat calvarial bone defect model, the osteogenic capacity of BIE was evaluated using a collagen type I-impregnated BM (Col-BM) composite. It is shown that Col-BM significantly promoted new bone formation in the critical-size bone defect areas. Taken together, this is the first study that investigated the influence of the BIE on osteogenesis, osteoimmunology, and in situ bone tissue engineering. The innate osteoinductive potential of inorganic bone components, both in vitro and in vivo, not only expands the understanding of the BIE on osteogenesis but also benefits future biomaterials engineering for bone tissue regeneration.
Postsystolic Shortening by Speckle Tracking Echocardiography Predicts Cardiovascular Events and Death in the General Population
Authors: Nanna Boline Lindhardt, Mats Christian Højbjerg Lassen, Kristoffer Grundtvig Skaarup, Niklas Dyrby Johansen, Gorm Boje Jensen, Peter Schnohr, Rasmus Møgelvang, Tor Biering-Sørensen
Journal: JACC. Cardiovascular imaging (2023)
Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy
Authors: Ruth Owen, Rachel Buchan, Michael Frenneaux, Julian W.E. Jarman, Resham Baruah, Amrit S. Lota, Brian P. Halliday, Angharad M. Roberts, Cemil Izgi, Harriette G.C. Van Spall, Erin D. Michos, John J.V. McMurray, James L. Januzzi, Dudley J. Pennell, Stuart A. Cook, James S. Ware, Paul J. Barton, John Gregson, Sanjay K. Prasad, Upasana Tayal
Journal: JACC Heart Failure (2023)

Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. We conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P < 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.
Can Four-Dimensional Computed Tomography Assess Dynamic Changes in Lung Volumes in Mechanically Ventilated Patients?
Authors: Shinshu Katayama, Ken Tonai, Kie Nakamura, Misuzu Tsuji, Shinichiro Uchimasu, Atsuko Shono, Masamitsu Sanui
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Can Four-Dimensional Computed Tomography Assess Dynamic Changes in Lung Volumes in Mechanically Ventilated Patients?." American Journal of Respiratory and Critical Care Medicine, 209(5), pp. 592–595
The Power of Three: Nanomaterials for Natural Killer (NK) Cell Immunoengineering Maximize Their Potency if They Exploit Multireceptor Stimulation
Authors: Helena Dodd, Nadia Guerra, Iain E. Dunlop
Journal: Advanced Healthcare Materials (2023)

Many emerging cancer treatments are immunotherapies that modulate Natural Killer- (NK) or T cell activation, posing a challenge to develop immunoengineering nanomaterials that improve on the performance of molecular reagents. In physiological activation, multiple immunoreceptors signal in consort; however, current biomaterials do not replicate this. Here, NK cells are created for the first time, activating bionanomaterials that stimulate >2 immunoreceptors. Nanoclusters of monoclonal antibodies (mAb), templated by nanoscale graphene oxide sheets (NGO) (≈75 nm size), are exploited. To inform nanoreagent design, a model system of planar substrates with anchored mAb is first investigated. Combining mAb that stimulates three NK cell activating receptors (αNKP46 + αNKG2D + αDNAM-1), activated NK cells act more potently than any single receptor or pair. Applying this insight, an NGO-mAb nanocluster combining three distinct mAb: NGO-mAb(αNKP46 + αNKG2D + αDNAM-1) is created. This construct is potent and outperforms single-receptor-simulating nanoclusters, activating nearly twice as many NK cells as NGO-mAb(αNKP46) at a similar mAb dose or delivering similar activation at 10× lower dosage. Further, NGO-mAb are more potent than planar substrates for both single- and triple-mAb stimulation. These results imply a new concept for immunoengineering biomaterials: both nanoclustering and multi-receptor stimulation should be incorporated for maximum effect.
Prevalence, Diagnostic Utility and Associated Characteristics of Bronchodilator Responsiveness
Authors: Richard Beasley, Rod Hughes, Alvar Agusti, Peter Calverley, Bradley Chipps, Ricardo del Olmo, Alberto Papi, David Price, Helen Reddel, Hana Müllerová, Eleni Rapsomaniki
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear.
The Value of Not Intubating Comatose Patients With Acute Poisoning
Authors: Zaffer Qasim, Jeanmarie Perrone, M. Kit Delgado
Journal: JAMA (2023)

Yonathan Freund, MD, PhD; Damien Viglino, MD, PhD; Marine Cachanado, MSc; Clémentine Cassard, MD; Emmanuel Montassier, MD, PhD; Bénedicte Douay, MD; Jérémy Guenezan, MD, PhD; Pierrick Le Borgne, MD; Youri Yordanov, MD, PhD; Armelle Severin, MD; Mélanie Roussel, MD; Matthieu Daniel, MD; Adrien Marteau, MD; Nicolas Peschanski, MD, PhD; Dorian Teissandier, MD; Richard Macrez, MD, PhD; Julia Morere, MD, PhD; Tahar Chouihed, MD, PhD; Damien Roux, MD, PhD; Frédéric Adnet, MD, PhD; Ben Bloom, MD; Anthony Chauvin, MD, PhD; Tabassome Simon, MD, PhD